STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass.
STAT3 regulates monocyte TNF-alpha production in systemic inflammation caused by cardiac surgery with cardiopulmonary bypass.
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DOI：
10.1371/journal.pone.0035070
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Jansen NJ
中科院分区：
文献类型：
--
作者：
de Jong PR;Schadenberg AW;van den Broek T;Beekman JM;van Wijk F;Coffer PJ;Prakken BJ;Jansen NJ
心脏搭桥术（CPB）引发了一种受控的全身性炎症反应，其特征在于细胞因子风暴、单核细胞增多和瞬时单核细胞活化。然而，单核细胞对Toll样受体（TLR）介导的激活的反应性在整个术后过程中降低。本研究的目的是确定参与血浆介导的LPS诱导的单核细胞产生肿瘤坏死因子（TNF）-α的抑制的主要信号通路。入组了接受CPB辅助手术矫正单纯先天性心脏病的儿科患者（n = 38）。 在连续时间点分离外周血单核细胞（PBMC）和血浆样本。将患者血浆样品加回术前获得的单核细胞中，用于离体LPS刺激，并通过流式细胞术测量TNF-α和IL-6的产生。通过Western印迹法评估患者血浆中LPS诱导的p38丝裂原活化蛋白激酶（MAPK）和核因子（NF）-κB活化。使用细胞渗透性肽抑制剂来阻断STAT 3信号传导。我们发现，无论术前地塞米松治疗如何，术后4小时获得的血浆样本均有效抑制LPS诱导的TNF-α，但不抑制单核细胞合成IL-6。这与p38 MAPK活化或IκB-α降解的减弱无关。然而，在存在抑制性患者血浆的情况下，IL-10/STAT 3通路的消除恢复了LPS诱导的TNF-α产生。我们的研究结果表明，STAT 3信号转导在体内系统性炎症过程中下调人单核细胞TNF-α的合成中起着至关重要的作用。因此，STAT 3可能是以全身炎症为特征的临床综合征的药物干预的潜在分子靶点。
Cardiopulmonary bypass (CPB) surgery initiates a controlled systemic inflammatory response characterized by a cytokine storm, monocytosis and transient monocyte activation. However, the responsiveness of monocytes to Toll-like receptor (TLR)-mediated activation decreases throughout the postoperative course. The purpose of this study was to identify the major signaling pathway involved in plasma-mediated inhibition of LPS-induced tumor necrosis factor (TNF)-α production by monocytes. Pediatric patients that underwent CPB-assisted surgical correction of simple congenital heart defects were enrolled (n = 38). Peripheral blood mononuclear cells (PBMC) and plasma samples were isolated at consecutive time points. Patient plasma samples were added back to monocytes obtained pre-operatively for ex vivo LPS stimulations and TNF-α and IL-6 production was measured by flow cytometry. LPS-induced p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB activation by patient plasma was assessed by Western blotting. A cell-permeable peptide inhibitor was used to block STAT3 signaling. We found that plasma samples obtained 4 h after surgery, regardless of pre-operative dexamethasone treatment, potently inhibited LPS-induced TNF-α but not IL-6 synthesis by monocytes. This was not associated with attenuation of p38 MAPK activation or IκB-α degradation. However, abrogation of the IL-10/STAT3 pathway restored LPS-induced TNF-α production in the presence of suppressive patient plasma. Our findings suggest that STAT3 signaling plays a crucial role in the downregulation of TNF-α synthesis by human monocytes in the course of systemic inflammation in vivo. Thus, STAT3 might be a potential molecular target for pharmacological intervention in clinical syndromes characterized by systemic inflammation.
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